T cell responses to the putative dominant autoepitope in primary biliary cirrhosis (PBC)

PBC is characterized by T cell-mediated destruction of the biliary epitheli al cells lining the small intrahepatic bile ducts. The E2 and E3 binding pr otein (E3BP (protein X)) components of pyruvate dehydrogenase complex (PDC) are disease-specific autoantigens in PBC. Attempts to localize the T cell autoepitopes within PDC-E2 have, however, generated contradictory results. One study has suggested the presence of T cell epitopes throughout PDC-E2, whilst another has identified a single dominant 14 amino acid T cell epitop e (p163) spanning the lipoic acid binding lysine residue in the inner lipoy l domain (ILD) of PDC-E2. The aim of the current study was to determine the prevalence of T cell responses to p163 and PDC-E2 ILD, and the role played by lipoylation of these antigens in their immunogenicity, in a UK PBC popu lation. We found that the majority of the PBC patients showing a 6-day peri pheral blood T cell proliferative response to native human PDC also respond ed, in a MHC class II-restricted fashion, to biochemically purified PDC-E2 and E3BP (which co-purify) (9/10 positive (SI > 2.76), mean SI 5.74 +/- 5.0 4 (PDC-E2/E3BP) versus 6.67 +/- 3.84 (PDC), P = NS), implying that the impo rtant PBC-specific T cell epitopes are contained within the PDC-E2 or E3BP components of PDC. Only a minority of patients responsive to PDC, however, responded to either lipoylated recombinant PDC-E2 ILD (4/10 positive, mean SI 1.98 +/- 1.24, P < 0.005 versus PDC response) or lipoylated p163 (4/12 p ositive, mean SI 1.90 +/- 1.58, P < 0.001). The lipoylation state did not a ffect the T cell response to either ILD or p163. Our findings suggest that in some UK patients with PBC there are immunodominant T cell autoepitopes w ithin PDC-E2/E3BP which are outside the ILD of PDC-E2.